School of Chemistry - Theses

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    Discovery and analysis of sulfosugar metabolic pathways
    Li, Jinling ( 2024-01)
    Sulfosugars are prevalent in the natural world, indicating the likelihood of metabolic pathways existing for their breakdown. An abundant sulfosugar is sulfoquinovose (SQ), which is produced by most photosynthetic organisms, constitutes a large organosulfur pool akin in magnitude to the amino acids cysteine and methionine, and plays a significant role in the biogeochemical sulfur cycle. Six sulfoglycolytic and sulfolytic pathways for the breakdown of SQ have been discovered in recent years. One of the major pathways is the sulfoglycolytic Entner-Doudoroff (sulfo-ED) pathway, which was first demonstrated in the Pseudomonas putida strain SQ1, a bacterium isolated from freshwater sediment. In Chapter Two, we report that the sulfo-ED pathway is operative in an important soil bacterium, Rhizobium leguminosarum SRDI565 (SRDI565). This bacterium can grow on SQ or SQ-glycerol using a sulfoglycolytic pathway to produce sulfolactate (SL). Comparative proteomic and metabolomics analysis support the use of this pathway in SRDI565, and we show that this organism encodes a sulfoquinovosidase (SQase) that can cleave glycosides of SQ. Interestingly, small amount of fructose-6-phosphate and glucose-6-phosphate were detected as metabolites indicating that growth on SQ also involves gluconeogenesis in SRDI565. In Chapter Three, we studied one of the key enzymes in the SRDI565 sulfo-ED pathway, sulfolactaldehyde dehydrogenase (SLADH). We show that this enzyme can oxidize SLA using both NAD+ and NADP+ and operates through a rapid equilibrium ordered mechanism. Surprisingly, we found that SLA dehydrogenase stereo specifically catalyzes only half amount of the SLA, and we suspected it is the D-SLA by the NMR data. We report the 3D structure of the enzyme bound to NADH by using cryo-EM and propose the organosulfonate binding residues in the active site. Based on these data, we hypothesized a catalytic mechanism for SLADH. Sequence based homology searches revealed potential homologs of SLADH in assorted sulfoglycolytic gene clusters across bacterial species, mainly within the phyla Actinobacteria, Firmicutes, and Proteobacteria. In Chapters Four and Five, the MultiGeneBLAST tool was used to discover two clusters of genes encoding proteins that are homologous to the sulfolytic sulfoquinovose monooxygenase (sulfo-SMO) pathway enzymes but lack a candidate SQase. One is in Rhodoferax aquaticus sp. and the other is in Marinovum sp. Instead, Rhodoferax aquaticus sp. contains an uncharacterized GH31 subfamily 2 protein (RaGH31) and Marinovum sp. contains an undefined GH13 subfamily 23 protein (MsGH13). We studied the biochemical properties of these two enzymes and show they are both active on 4-nitrophenyl alpha-D-glucopyranoside (PNPGlc) as well as alpha-glucosidic linkages in disaccharides. RaGH31 is active on maltose, sucrose, trehalose, nigerose while MsGH13 is active on maltose, sucrose, nigerose, trehalose, isomaltose, and kojibiose. We developed models of the 3D structures for these two enzymes and their active sites using AlphaFold. In Chapter Six, we explored the degradation of another sulfosugar, sulfofucose. We chemically synthesized sulfofucose and isolated a bacterium from soil collected on the banks of Merri Creek that can grow on sulfofucose as sole carbon source. Genome sequencing revealed it belongs to Paracoccus onubensis, and we named it strain Merri. Comparative proteomics suggests that sulfofucose breakdown involves enzymes analogous to those in the sulfo-EMP pathway. We have expressed a likely sulfofructose-1-phosphate (SFP) aldolase and found it reacts with the related compound, SFP. The 3D structure of this aldolase determined by X-ray crystallography showed significant similarity to the aldolase from the sulfo-EMP pathway. Therefore, we proposed a patchwork sulfofucose catabolism pathway involving a sulfo-EMP pathway and short-chain organosulfonate biomineralization pathway.
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    Self-Healing Paint: Functionalizing an Acrylic Coating with a Quadruple Hydrogen Bonding Network
    Beach, Maximilian Arthur ( 2023-12)
    Paints are coatings which serve to both protect surfaces from damage and impart a variety of aesthetic qualities. They are composed of a matrix of interlocking hydrophobic acrylic polymers which constitute the body of the coating, while binding together a myriad of other additives including pigment particles. Paints represent the majority fraction of a vast global coatings market, and, like all coatings, are exposed to a variety of stresses that can lead to long term damage in the form of microcracks. To date, the only method to repair such damage is to simply replace the paint with a new coat, which is expensive and time consuming. Self-healing technology is perhaps the most promising solution to this problem, as it offers the ability to heal damage spontaneously and without external diagnosis. However, neither a self-healing paint, nor any viable self-healing acrylic coating currently exists. The work presented herein represents a 3-and-a-half-year research effort to successfully design both a self-healing acrylic coating and a feasible self-healing paint. The strong quadruple hydrogen bonding unit 2-ureido-4[1H]-pyrimidinone (UPy) was incorporated into an acrylic coating to form a hydrogen bonding network. Upon damage to the coating, the strong attractive forces between the broken UPy units in the network prompted self-healing through polymer rearrangement and the reformation of UPy–UPy bonds. This was achieved first through the design of an UPy functionalized acrylic monomer with a long amphiphilic spacer. This monomer, at a concentration of only 2.5 wt%, was able to successfully imbue a typical acrylic coating with efficient self-healing (~25%) at room temperature. Then, in order to enhance self-healing efficiency, a UPy functionalized crosslinker system with exotic architecture was designed. One crosslinker design in particular successfully enhanced self- healing efficiency by over 10%. Finally, in collaboration with the international paint company DuluxGroup, this self-healing acrylic coating design was incorporated into a paint formulation according to the product range WeathershieldTM. The resulting UPy-Paint was subjected to range of industry specific paint tests, and its optical and mechanical self-healing performance was evaluated.
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    Sample Pretreatment within Microfluidic Paper-based Analytical Devices (µPADs) with Optimised Colorimetric Detection
    Uhlikova, Natalie ( 2023-08)
    The work detailed here is conducted in the area of microfluidic paper-based analytical devices (uPADs), with emphasis on sample pretreatment for simplified and more sensitive sample analysis. Dimensions and thickness of uPADs typically do not exceed those of a credit card. Such devices consist of a few layers of filter paper with patterned hydrophilic and hydrophobic zones, the former impregnated with reagents. Reagent(s) deposited on the detection zone are designed to change colour after sample is applied. By recording a digital image of the colour change of before and after the sample insertion, analyte concentration can be derived. Common media for capturing the colour change are scanners or mobile phones. The small size of uPADs, their ease of operation, speed of analysis and portability, make them well-suited tools for in-situ quantitative analysis. At first, the foundations of the colorimetric detection method were investigated and guidelines formulated for optimum colour recording by scanning devices, namely flatbed and sheet-fed scanners. Next, two types of sample pretreatment were explored: analyte derivatisation and preconcentration. The former was implemented in a uPAD for speciation of inorganic nitrogen species in environmental waters and soil leachates, application of the latter was demonstrated for copper detection in tap and environmental waters.
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    Tailored Growth of WS2 for AFM Sensing Applications
    Rokhsat, Eliza ( 2023-11)
    Two-dimensional layered transition metal dichalcogenides (TMDs) such as MoS2, WS2, MoSe2, and WSe2 are garnering considerable attention for their potential in chemical sensing applications. This thesis investigates the influence of source sublimation temperature and source-to-substrate distance on the nucleation and growth kinetics of WS2. A novel approach is developed to fabricate highly luminescent WS2 monolayers, which exhibit adjustable composition, optical, morphological, and electrical properties. Incorporating these WS2 layers as sensing materials, surface potential measurements have revealed critical connections between intrinsic defects and the chemical sensing capabilities of the monolayers. The thesis also delves into the challenges that need to be addressed to harness TMD monolayers effectively as molecular sensing materials, potentially enriching our understanding of chemical sensors. Additionally, this study examines nanomechanical detection using microcantilevers, exploring the fundamental mechanisms, benefits, and drawbacks of both methods to provide a comprehensive view of their efficacy, rapid response times, and selectivity in molecular sensing.
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    Valence Tautomerism in Cobalt-Dioxolene Complexes: A Combined Computational and Experimental Study
    Mohamed Zahir, Fathima Zahra ( 2023-12)
    Switchable molecules afford potential applications for the advancement of functional materials in sensing and display to molecular memories. The ability to identify the occurrence of switching along with their precise properties computationally, before synthesis, is a significant advancement. This thesis presents a series of studies on a computational and experimental investigation of valence tautomeric (VT) behavior in cobalt-dioxolene complexes. Density functional theory (DFT) methods have been effectively utilized for the exploration of VT characteristics of neutral [Co(3,5-dbdiox)(3,5-dbsq)(N2L)] (3-5-dbdiox/ 3,5-dbsq- = 3,5-di-tert-butyldioxolene/semiquinonate; N2L = diimine ancillary ligand) family of VT complexes. Appropriate DFT methods are selected via a rigorous benchmarking process to explore various properties including electronic structure, electronic absorption spectral transitions, spin-state energetics, and the impact of ancillary ligands on the transition temperatures (T1/2) of the complexes. From this analysis, the extent of sigma donation and pi back bonding effects are quantified, which led to a simple model for the prediction of experimental T1/2 values of the complexes, by determining the lowest unoccupied molecular orbital (LUMO) energy of the corresponding diimine ligand. Understanding important concepts in VT equilibria requires an extensive and unified analysis of the existing molecules. The study presents a robust approach for the analysis of diverse cobalt-dioxolene complexes, which involves a quantitative DFT-based benchmark study with reliable quasi-experimental references. Around 50 different cobalt-dioxolene complexes are considered for this study that encompassed both cationic [Co(diox)(N4L)]+ and neutral [Co(diox)(sq)(N2L)] (diox = generic dioxolene, N2L/N4L = bidentate/tetradentate N-donor ancillary ligand) family of complexes. The best-performing method not only accurately captured the experimental behavior of all the reported complexes but also afforded the prediction of potential VT complexes. The predictions are verified by the synthesis and experimental investigation of three new complexes, two of which exhibit thermally-induced VT, while the third remains in the LS-CoIII-cat form across all temperatures, in agreement with the predictions. The study also enabled the elucidation of the origin of the solvent effects for VT equilibria, which has not been definitively known. The analysis revealed that VT transition temperatures in various solvents are modulated via solvent stabilization energy and change in dipole moment. The study presents the impact of valence tautomeric switching characteristics under temperature and pressure through a combined approach of computational and experimental investigations. Previously reported [Co(3,5-dbdiox)(Mentpa)][PF6].(toluene) (Mentpa = tris(2-pyridylmethyl)amine where n = 2 and 3, indicates methylation of the 6-position of the pyridine rings) are investigated by single crystal X-ray diffraction under temperature and pressure. The study showed that high pressure induces unique behavior in the complexes compared to the thermal counterparts. The thermally inactive HS-CoII-sq (high-spin CoII-semiquinonate) [Co(3,5-dbdiox)(Me3tpa)][PF6].(toluene) compound, displayed VT transition under applied pressure. Various computational approaches including quantum mechanochemical methods are utilized for rationalizing the experimental observations. Density functional theory calculations revealed that compression assists in overcoming the spin-state energy requirements. The best-performing DFT approaches identified for mononuclear neutral and cationic cobalt-dioxolene complexes are utilized for the investigation of VT characteristics of dinuclear cobalt-dioxolene complexes. Throughout the series of studies, it is identified that, regardless of the type of cobalt-dioxolene (mononuclear neutral, mononuclear cationic or dinuclear), thermal VT interconversions occur with experimental enthalpy change of 20 – 70 kJ mol-1. This criterion based on experimental enthalpy change, is utilized for understanding the thermal accessibility of the complexes, serving as a key parameter in identifying various transition profiles in dinuclear cobalt-dioxolene VT complexes. The study facilitates the identification of potential VT complexes with specific properties including transition temperature, sensitivity to the environment, and characteristics of the transition. This enables the in-silico design of VT complexes for a range of potential applications.
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    The Development of Methods to Install and Diversify Carbonyl Derivatives via Radical Intermediates
    Guan, Xiaocong ( 2023-10)
    Alkyl carboxylic acids play a crucial role as pharmacophores in drug molecules. The current method for obtaining alkyl carboxylic acids primarily limited to the hydroxylation of carboxylic acid derivatives. Therefore, developing innovative approaches to directly install carboxylic acid is very meaningful for pharmaceutical molecular synthesis. The most efficient way to incorporate this motif is through direct carboxylation of the substrate. Traditionally approach involves preparing highly reactive Grignard reagents from alkyl halides, which had limitations in terms of functional group tolerance. Previous work by the Polyzos group demonstrated that transition metals such as palladium could selectively activate C(sp3)-H bonds by forming palladacycle complexes with the assistance of directing groups. However, the insertion of CO2 into the palladacycle was found to be unfavourable. Therefore, CO2 surrogate was employed to explore direct C(sp3)-H carboxylation based on the palladacycle complex. Another approach to construct alkyl carboxylic acids is through the hydrocarboxylation of double-bond systems, which can be achieved by using umpolung strategy. Although reaction systems utilizing photochemistry and electrochemistry have been reported for the hydrocarboxylation of double bonds, these methods are specific to certain double bond system, and most electrochemical methods require sacrificial anodes to stabilize the carboxylic anion. Chapter 1 is a literature review, in which two direct carboxylic acid installation approaches, C(sp3)-H carboxylation and hydrocarboxylation of double bond systems, are introduced. The challenges of C(sp3)-H carboxylation and limitations of current hydrocarboxylation examples were highlighted. Next, the principles of photocatalysis, electrochemistry and continuous flow chemistry are discussed. Finally, the general objectives of this PhD thesis are subsequently elaborated. Chapter 2 explores direct C(sp3)-H carboxylation using carbon tetrabromide as a CO2 surrogate. This approach builds upon previous work by the Polyzos group on auxiliary-directed C(sp3)-H arylation through synergistic photoredox and palladium catalysis. To check the feasibility of this reaction design, the exploration was started with the palladacycle, which is the key intermediate for the previous arylation reaction. During the exploratory studies, both carboxylation and carbonylation product were obtained under the photoredox reaction system. Although the selectivity issue was eliminated by adopting a direct excitation of the palladacycle complex, which favours the annulation pathway, only moderate yield was obtained. Chapter 3 investigates the hydrocarboxylation of double bonds to access alkyl carboxylic acid construction. Electrochemical approach was employed to address the challenging reduction of the double bonds. Furthermore, due to the CO2 gas was employed as the carboxylation source, the continuous flow technology was incorporated to better manage the multiphase reaction, which could also potentially circumvent the decarboxylation issue by precisely control the residence time. Following optimization, the reaction exhibits excellent functional group tolerance and this hydrocarboxylation procedure broadly covers C=N, C=O, C=C systems. Mechanistic study indicates the carboxylic acids are primarily formed through the nucleophilic attack of the carbanion on the CO2. In Chapter 4, a chemoselective reduction procedure of carbonyl compounds in continuous flow was developed, based on the disparities observed in the primary byproducts during the hydrocarboxylation process of C=N and C=O bonds described in Chapter 3. The umpolung strategy, wherein the ketyl undergoes the radical polar crossover under specific flow-electrochemical conditions, is employed to solve the homocoupling issue in the carbonyl reduction process. Both aromatic or aliphatic ketones and aldehydes, are viably reduced to the corresponding alcohols in good to excellent yields with broad functional group tolerance. Quantitative deuterium incorporation indicates the radical polar crossover was effectively achieved. Chapter 5 provides detailed experimental procedures and spectroscopic data for all isolated compounds throughout the thesis.
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    Toward the synthesis and analysis of selenium-containing glucocorticoid prodrugs
    Macdougall, Phoebe Eleanor. (University of Melbourne, 2007)
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    NMR studies of amyloid ab-peptide in membranes
    Lau, Tong Lay (Crystal) (University of Melbourne, 2006)
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    Gas Phase Chemistry of Iranium Ions with Unsaturated Carbon-Carbon Bonds
    Brydon, Samuel Charles ( 2023-10)
    The study of cyclic iranium ions has developed rapidly over the last few decades as control of stereoselective outcomes during the electrophilic functionalisation of alkenes is mostly determined by the configurational stability of these species. Trace nucleophiles such as solvent, counter-ions, or unreacted alkene may cause decomposition or racemisation of these intermediates as the electrophilicity of both the heteroatom and endocyclic carbons make them susceptible to nucleophilic attack. Mass spectrometry (MS) thus offers an alternative means by which to isolate these charged species and study their bimolecular reactivity in the gas phase. Generation of these ions was achieved by electrospray ionisation of precursors containing a suitably basic group beta to the heteroatom, which upon protonation would fragment either in-source or following collision-induced dissociation of the pseudomolecular ion to give the heterocyclic three-membered ring. The multistage MS capabilities of a modified linear ion trap were utilised to isolate the iranium ion and observe its reactivity with neutral alkenes or alkynes. Changing the chalcogen (Ch) from sulfur to selenium to tellurium had a significant effect on the partitioning between attack at the heteroatom or ring-opening at carbon. Telluriranium ions underwent exclusive pi-ligand exchange with direct transfer of the tellurenium cation to the neutral reagent in a series of identity reactions, whilst all thiiranium ions studied only showed addition products from ring-opening by the neutral species. The reactivity of seleniranium ions towards alkenes partitioned between these two pathways with electron-donating groups on the heteroatom favouring the former, whilst the latter was promoted by electron-withdrawing groups. Computational studies into the pi-ligand exchange reaction revealed a Huckel pseudocoarctate transition state with a disconnection in the orbital array during the bond-breaking and bond-forming step. Extension to the haliranium ions showed kinetics of ion-molecule reactions with both cyclic and linear alkenes proceeding at the collision rate with iodiranium ions reacting dominantly via pi-ligand exchange, but bromiranium ions underwent carbocation-based fragmentation following ring-opening. Conjugation of the double bond to methyl esters suppressed heteroatom attack on iodiranium ions and only gave allylic stabilised oxocarbenium ions. The partitioning between these two reaction channels could be tuned by substituting inductively electron donating methyl groups onto the carbon-carbon double bond or entirely reverted to pi-ligand exchange by disrupting the conjugation with a methylene spacer enabling differentiation between three isomeric unsaturated methyl esters. Stability of the unsaturated irenium ions was examined by natural bond orbital theory to study (anti)aromaticity in these species. This approach revealed the antiaromatic nature of halirenium ions due to repulsion between the lone pairs and filled pi-orbital of the endocyclic double bond, and non-aromatic nature of the chalcogen irenium ions due to introduction of stabilising pi(C=C) - sigma*(Ch-R) hyperconjugative interactions. These species were generated in the gas phase for the first time by ion-molecule reactions of iranium ions with alkynes. The selenirenium ion structure assignment was strongly supported by cross-over experiments showing selenyl transfer to another alkyne, whilst the proposed iodirenium ion showed different reactivity to that of the open beta-iodovinyl cation produced upon reaction with phenylacetylene.